This application relates to products for the treatment of viral infections, in particular HIV infections, using the known antiviral compounds efavirenz (tradename Sustiva, also known as EFV), emtricitabine (tradename Emtriva, also known as FTC) and tenofovir DF (disoproxil fumarate, also known as TDF) (tradename Viread, sold in combination with emtricitabine under the tradename Truvada).
The Truvada product is produced by wet granulation of emtricitabine and tenofovir DF (WO 04/64845), which under the circumstances produces a chemically stable dosage form. This product does not contain efavirenz.
HIV therapy using efavirenz as well as emtricitabine and tenofovir DF has been considered desirable. (hereafter “triple combination”; see WO 04/64845). Manufacturing a commercially viable triple combination product, however, would require that the final product meet stringent FDA requirements for bioequivalence to the commercial products, Viread (tenofovir disoproxil fumarate), Emtriva (emtricitabine), and Sustiva (efavirenz), and that the tablet be of suitable size for patients to easily swallow.
Initial efforts to simply combine the three drugs (active pharmaceutical intermediates, or APIs) into a unitary, essentially homogeneous composition manufactured by wet granulation failed to produce a chemically stable tablet. The tenofovir DF in this combination tablet was highly unstable and rapidly degraded in stability studies. The efavirenz formulation was unexpectedly incompatible with tenofovir DF, a result now attributed to the surfactant (sodium lauryl sulfate) found in the efavirenz portion of the formulation.
Another attempt was made to produce the triple combination, this time using a dry granulation of the three part combination and omitting the surfactant. This resulted in a tablet that failed to achieve bioequivalence with respect to efavirenz in human clinical trials. The peak efavirenz concentration in the blood stream and total drug exposure (Cmax and AUC) were both below the parameters determined for the commercial comparator, Sustiva (efavirenz) tablets. The inventors concluded that at least the surfactant in the triple combination (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets was necessary to achieve bioequivalence to Sustiva.
Next, combination tablets were manufactured by wet granulating the efavirenz component with the surfactant and other excipients, separately manufacturing the Truvada component using dry granulation, mixing the granulates together, compressing the mixture into tablets, and then film-coating the tablets. Unexpectedly, this approach also failed to produce the desired bioequivalence in between the commercial product, Sustiva (efavirenz), and clinical trial material (i.e., proposed commercial triple combination product). A novel and inventive step was needed to overcome the shortcomings of more straight-forward approaches to a triple combination dosage form.
As described further in copending U.S. Ser. No. 60/771,279 (filed of even date and expressly incorporated herein by reference) the stability and bioequivalence objectives for the triple combination tablet ultimately were achieved in an exemplary embodiment by dry granulating the emtricitabine/tenofovir disoproxil fumarate component, wet granulating the efavirenz component and, rather than using the straight-forward process of simply combining the granulates, instead organizing the granulates to produce a multilaminate dosage form, one component containing the emtricitabine/tenofovir disoproxil fumarate element, the other containing the efavirenz element. This minimized the contact of the tenfovir DF with surfactant, yet maintained the efavirenz excipients and process features that contributed to achieving bioequivalence.
An additional obstacle to the triple combination dosage form was presented, and it is this problem that the present application is directed to solving. As noted above, simply combining the excipients present in the known commercial products, Truvada and Sustiva tablets, was undesirable because the resulting tablet would contain the entire excipient load of the known tablets and thus would be large for a single tablet and present a dosage form that was difficult to swallow and therefore inconvenient for patient use. It thus was an objective to prepare a highly concentrated preparation of emtricitabine and tenofovir DF, which by reducing the amount of excipients in the preparation, would contribute to an overall reduction in the size of the triple combination tablet. However, simply reducing the proportion of excipient to API and wet granulating in accord with the known process was not effective in producing a stable composition.
While the prior art reports the successful manufacture of chemically stable Truvada preparations (WO04/64845) by wet granulation, these preparations typically contain relatively low proportions of excipient to API, on the order of to 1:1. Wet granulation of a preparation in which the proportion of excipient had been reduced to manageable amounts for a triple combination tablet unexpectedly resulted in a chemically unstable preparation. Without being held to any particular theory of operation, the inventors believe that so much water is required in the wet granulation of efavirenz (which has relatively low solubility in comparison to emtricitabine and tenofovir DF) that the latter two APIs dissolve into a eutectic mixture. These dissolved APIs, when dried during granulation, form a glassy or amorphous product, which is chemically unstable in comparison to the crystalline API. In the prior process enough excipient is present to ameliorate the effect of the excess water is, but this was not feasible when the ratio of excipient to API is reduced to a level required for a manageable triple combination oral dosage form.